Multiphasic MDCT Enhancement Pattern of Hepatocellular Carcinoma Smaller Than 3 cm in Diameter: Tumor Size and Cellular Differentiation

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1 Gastrointestinal Imaging Original Research Yoon et al. MDCT of Hepatocellular Carcinoma Gastrointestinal Imaging Original Research Soon Ho Yoon 1 Jeong Min Lee 1,2 Young Ho So 1 Sung Hyun Hong 3 Soo Jin Kim 1 Joon Koo Han 1,2 Byung Ihn Choi 1,2 Yoon SH, Lee JM, So YH, et al. Keywords: enhancement pattern, hepatocellular carcinoma, MDCT DOI: /AJR Received September 11, 2008; accepted after revision June 4, Department of Radiology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, , Korea. Address correspondence to J. M. Lee (leejm@radcom.snu.ac.kr). 2 Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Korea. 3 Department of Radiology, Daerim St. Mary s Hospital, Seoul, Korea. WEB This is a Web exclusive article. AJR 2009; 193:W482 W X/09/1936 W482 American Roentgen Ray Society Multiphasic MDCT Enhancement Pattern of Hepatocellular Carcinoma Smaller Than 3 cm in Diameter: Tumor Size and Cellular Differentiation OBJECTIVE. The purpose of this study was to evaluate according to size and degree of cellular differentiation the multiphasic MDCT enhancement pattern of hepatocellular carcinoma (HCC) smaller than 3 cm in diameter in patients with cirrhosis. MATERIALS AND METHODS. In 155 consecutively registered patients (126 men, 29 women; mean age, 58.4 years), 204 pathologically proven HCCs smaller than 3 cm were detected at multiphasic MDCT. Three radiologists in consensus classified the relative attenuation of the tumors compared with the surrounding liver parenchyma as hyperattenuation, isoattenuation, or hypoattenuation on biphasic (n = 86) and triphasic (n = 69) CT scans. RESULTS. The prevalent enhancement patterns of HCC differed depending on tumor size. The prevalent pattern of HCC measuring mm was arterial hyperattenuation with venous washout (47%, 47/101). The prevalent enhancement patterns of HCC smaller than 10 mm and HCC measuring mm were isoattenuation during the arterial and portal venous phases (29%, 6/21) and hyperattenuation and isoattenuation during the arterial and portal venous phases (33%, 27/82). The typical HCC enhancement pattern (arterial hyperattenuation with venous washout) was identified in 48% (67/141) of the moderately and poorly differentiated HCCs and in 13% (8/63) of well-differentiated HCCs. CONCLUSION. The prevalent enhancement patterns of HCC smaller than 3 cm on multiphasic MDCT scans differed depending on tumor size and cellular differentiation. HCCs smaller than 2 cm and well-differentiated HCCs frequently had atypical enhancement patterns. H epatocellular carcinoma (HCC) is the fifth most common tumor worldwide, is one of the leading causes of cancer-related death, and has an increasing incidence worldwide [1]. Cirrhosis, particularly cirrhosis-related hepatitis B and hepatitis C virus infections, is the greatest and most widely known risk factor for HCC [2, 3]. Early diagnosis of small HCC has become a principal objective in abdominal imaging because several potentially curative treatment options, such as liver transplantation, surgical resection, and local ablation therapy, can be successfully used to improve outcome if the HCC detected is small, that is, less than 2 3 cm in diameter [1 4]. However, although the widespread use of screening and surveillance programs, including those that entail measurement of α-fetoprotein concentration and ultrasound, has increased the possibility of detecting small hepatic nodules, diagnosis, especially of nodules smaller than 2 cm in diameter, remains a difficult task in clinical practice [5, 6]. Once a screening test has abnormal results or there is clinical suspicion that a patient may have HCC, imaging is important for the diagnosis and staging of this tumor [7]. The most reliable diagnostic tests are multiphasic MDCT and dynamic MRI, and the hallmark of HCC during CT and MRI is the presence of hyperattenuation in the arterial phase followed by delayed hypoattenuation or hypointensity (washout) of the tumor in the portal venous and delayed phases [8]. Because of increasing experience with imaging techniques, clinical practice guidelines for evaluation of HCC were published in 2001 by the European Association for the Study of the Liver [9] and in 2005 by the American Association for the Study of Liver Diseases [10]. The more recent recommendation by the latter organization is that if a tumor larger than 2 cm in diameter has typical features of HCC, that is, arterial hyper W482 AJR:193, December 2009

2 MDCT of Hepatocellular Carcinoma attenuation and washout in the portal venous or delayed phase of contrast-enhanced CT or MRI, a diagnosis of HCC may be made noninvasively. Furthermore, in patients with cirrhosis, masses measuring 1 2 cm in diameter that have typical enhancing features of HCC on both types of images can be diagnosed as HCC without biopsy [10]. Because the imaging criteria suggested in the European Association for the Study of the Liver and American Association for the Study of Liver Diseases guidelines for diagnosis of HCC are based only on vascular findings, there must remain a number of small HCCs and well-differentiated HCCs lacking typical vascular changes. Studies [11, 12] have shown that the absence of discordant vascularity at various imaging studies can mask identification of true hypovascular HCC. To our knowledge, the validity of the American Association for the Study of Liver Diseases guidelines based on tumor diameter and cellular differentiation has rarely been studied [13]. The purposes of this study were to evaluate the enhancement pattern of HCC smaller than 3 cm in diameter at multiphasic MDCT of a cirrhotic liver according to size and degree of cellular differentiation and to determine the frequency of typical arterial hyperattenuation and early venous washout of HCC depending on tumor size and cellular differentiation. Materials and Methods Patients Our institutional review board approved this retrospective study and waived the requirement for informed consent. The database records of the department of pathology from January 2001 through May 2007 were reviewed to identify the cases of patients with a pathologic diagnosis of cirrhosis and HCC. Among these patients, the study sample was selected on the basis of the following inclusion criteria: pathologic diagnoses of HCC smaller than 3 cm in diameter and cirrhosis [13 15]; available preoperative multiphasic MDCT scans obtained according to the standard protocol for dynamic liver CT; mean interval between pathologic diagnosis and CT no longer than 6 weeks [16, 17]; and no history of previous adjuvant treatment, such as trans catheter arterial chemoembolization, percutaneous ethanol injection, or radiofrequency ablation, of each pathologically diagnosed HCC. A total of 204 pathologically proven HCCs smaller than 3 cm in 155 consecutively registered patients were included in the study. The study group consisted of 126 men and 29 women (mean age, 58.4 years; range, years). The pathologic diagnosis of HCC was obtained in 29 cases through liver transplantation, in 91 cases through liver resection, and in 35 cases through core needle biopsy with an 18-gauge needle. Explanted livers were evaluated at 5-mm slice section intervals in the sagittal plane. The underlying causes of liver disease were hepatitis B virus infection (n = 117), hepatitis C virus infection (n = 23), combined hepatitis B and hepatitis C virus infection (n = 1), alcoholism (n = 5), and unknown factors (n = 9). Among the 155 patients, 126 patients had one HCC each, 17 had two HCCs, nine had three HCCs, and three patients had more than four HCCs. The tumors were categorized into three groups according to largest dimension of the HCC in the pathologic specimens: < 10 mm, mm, and mm. Cellular differentiation of HCC was assessed as good, moderate, and poor by one of two experienced liver pathologists. Image Acquisition Eighty-six patients underwent biphasic MDCT, that is, unenhanced phase, arterial phase, and portal venous phase, and 69 patients underwent triphasic MDCT, that is, unenhanced phase, arterial phase, portal venous phase, and equilibrium phase. The mean period between pathologic diagnosis and most recent CT examination was 19.9 days (range, 1 42 days). Because the data were gathered during the period when MDCT technology was developing rapidly, various CT scanners were used: 38 patients underwent imaging with a 4-MDCT scanner (MX8000, Marconi Medical Systems), 39 patients with an 8-MDCT scanner (LightSpeed Ultra, GE Healthcare), 52 patients with a 16-MDCT scanner (Sensation 16, Siemens Healthcare), and 26 patients with a 64-MDCT scanner (Brilliance 64, Philips Healthcare). CT scans were obtained along the craniocaudal plane. The respective scanning parameters used for the 4-, 8-, 16-, and 64-MDCT scanners were detector configuration, 4 2.5, , , and mm; slice thickness, 3.2, 2.5, 3, and 3 mm; reconstruction interval, 3, 2.5, 3, and 3 mm; table speed, 12.5, 13.5, 24, and 46.9 mm/rotation; 150, 250, 200, and 175 effective mas; rotation time, 0.5, 0.5, 0.5, and 0.75 second; 120 kvp; and matrix size, Therefore, although the acquisition times for each phase differed on the basis of liver size, the mean acquisition times for each phase were 8, 7.4, 4.17, and 3.2 seconds. A total of 120 ml of nonionic contrast material (iopromide, Ultravist 370, Bayer Schering Pharma) was injected into an antecubital vein at a rate of ml/s with a power injector (Envision CT, Medrad). The scan delay for the arterial phase was seconds (15 seconds for the 4- and 8-MDCT scanners, 17 seconds for the 16- MDCT scanner, 19 seconds for the 64-MDCT scanner) after achievement of 100-HU attenuation of the descending aorta measured with a bolustracking technique [18]. A 30- to 33-second scan delay (30 seconds for the 4- and 8-MDCT scanners, 33 seconds for the 16- and 64-MDCT scanners) after arterial phase acquisition was used for the portal venous phase acquisition. The equilibrium phase images of 69 patients with 75 HCCs were obtained 180 seconds after the start of contrast administration. The adequate timing of the arterial phase of MDCT was defined as intense hepatic arterial, mild portal venous, slight parenchymal, and no hepatic venous enhancement on CT images [19]. Image Analysis Image analysis had two steps: qualitative analysis and supplementary quantitative analysis of HCC. The qualitative and quantitative analyses were performed with information on the location of each HCC so that a lesion-by-lesion analysis could be performed at a PACS workstation (Maroview, Marotech). For the qualitative analysis of HCC, all images were retrospectively assessed in consensus by two attending radiologists, each with more than 5 years of clinical experience in hepatobiliary imaging. The readers were not blinded to the pathologic results, and in inconclusive cases, the lesions were located on the basis of the pathologic specimen. The scans were evaluated with both narrow (width, 150 HU; level, HU) and soft-tissue (width, 400 HU; level, HU) window settings. The attenuation of HCC was classified as hyperattenuation, isoattenuation, and hypoattenuation, compared with the surrounding liver parenchyma on arterial phase, portal venous phase, and equilibrium phase images. In homogeneously enhancing nodules, nodule attenuation on the arterial phase images was evaluated to determine the mean tumor attenuation. Heterogeneously enhancing lesions were classified as hyperattenuating when most of the solid tumor was enhanced [20]. On portal venous phase and equilibrium phase images, each lesion was subjectively evaluated for the presence of washout [10, 13, 21]. Washout was defined as occurring when any part of the lesion that was hyperattenuating on arterial phase images had a corresponding hypoattenuating area relative to the adjacent liver parenchyma on portal venous phase or equilibrium phase images. The enhancement patterns of HCC according to attenuation during the arterial and portal venous phases were classified as one of the following six types: hyperattenuation hyperattenuation, hyperattenuation isoattenuation, hyperattenua AJR:193, December 2009 W483

3 Yoon et al. tion hypoattenuation, isoattenuation isoattenuation, iso attenuation hypoattenuation, and hypoattenuation hypoattenuation. If it was difficult to determine tumor attenuation by visual inspection of arterial phase, portal venous phase, and equilibrium phase images, the results of quantitative analysis of the HCC were used as a reference. To maintain consistency, one radiologist not involved in the qualitative analysis performed all measurements on the arterial, portal venous, and equilibrium phase images. The regions of interest (ROIs) were determined by one of the authors. The quantitative analysis of HCC was performed to determine the tumor-to-liver attenuation difference, defined as the difference in attenuation between the tumor and the liver [22 24]. Attenuation values were obtained in a 0.3- to 2.2-cm 2 circular ROI. The ROI tumor values in the arterial, portal venous, and equilibrium phases were measured from the portion of the tumor that had the greatest attenuation on the arterial phase images. An attempt was made to maintain a tumor ROI of approximately 0.5 cm 2 (range, cm 2 ). Measurement of the attenuation in the hepatic parenchyma excluded visible hepatic and portal vessels, bile ducts, and artifacts. An attempt was made to maintain a constant ROI area of liver parenchyma of approximately 2.0 cm 2 (range, cm 2 ). At least three measurements were performed in each tumor and in the right and left lobes, and the results were averaged. When calcifications or cystic foci were found in a lesion or in the liver parenchyma, such regions were avoided in the ROI analysis. A difference of more than 10 HU in mean attenuation between the tumors and the hepatic parenchyma was considered meaningful [23, 25]. The difference in attenuation between each tumor and normal liver parenchyma was calculated. After the assessment of HCC attenuation, each HCC was categorized into an enhancement pattern according to the combination of attenuation in the arterial and that in the portal venous phase. The proportions of each enhancement pattern, arterial hyperattenuation, and venous washout were analyzed according to size and cellular differentiation. For patients with triphasic CT images, to determine the additional value of equilibrium phase imaging when equilibrium phase images were added to biphasic CT, the subgroups analysis of the proportion of images showing a typical enhancing feature of HCC, that is, arterial hyperattenuation followed by washout in the portal venous phase or equilibrium phase, was performed with various combinations of image sets, that is, a combined set of arterial and portal venous phase images, a combined set of arterial and equilibrium phase images, and a combined set of arterial, portal venous, and equilibrium phase images. Statistical Analysis Baseline characteristics of the hepatic tumors were expressed as mean ± SD. The chi-square test for categoric variables was used to analyze the prevalent enhancement pattern and percentage of tumors with arterial hyperattenuation or venous washout according to tumor size and cellular differentiation. Tumor size and cellular differentiation were evaluated as independent variables for the enhancement pattern of HCC through comparison of the incidence of typical enhancement pattern as follows: well-differentiated HCC smaller than 2 cm in diameter versus moderately or poorly differentiated HCC smaller than 2 cm, well-differentiated HCC larger than 2 cm versus moderately or poorly differentiated HCC larger than 2 cm, well-differentiated HCC smaller than 2 cm versus well-differentiated HCC larger than 2 cm, and moderately or poorly differentiated HCC smaller than 2 cm versus moderately or poorly differentiated HCC larger than 2 cm. A two-sided significance level of 5% was used for all analyses. The analyses were conducted with a statistical software package (SPSS 12.0, SPSS). TABLE 1: Mean Size of Hepatocellular Carcinoma According to Degree of Cellular Differentiation Variable Size group (cm) Well Differentiated Moderately Differentiated Poorly Differentiated (43) 11 (52) 1 (5) (44) 46 (56) NA (18) 79 (78) 4 (4) 101 Total 63 (31) 136 (67) 5 (2) 204 Mean size ± SD (cm) 1.57 ± ± ± ± 0.69 Note Values in parentheses are percentages. NA = not available. Total Results A total of 204 HCC nodules were analyzed in 155 patients. Twenty-one HCCs (10.3%) were smaller than 10 mm in diameter; 82 HCCs (40.2%) were mm in diameter, and 101 HCCs (49.5%) were mm in diameter. The mean diameter of all HCC nodules was 1.83 ± 0.69 cm. According to the cellular differentiation of HCC, 63 HCCs (30.1%) were well differentiated, 136 HCCs (66.7%) were moderately differentiated, and five HCCs (2.4%) were poorly differentiated. Fatty metamorphosis was found in 46 of the 204 HCCs (22.5%). Fatty metamorphosis was found in seven of the 21 HCCs (33.3%) smaller than 1 cm in diameter, 25 of the 82 HCCs (30.5%) measuring 1 2 cm, and 14 of the 101 HCCs (13.7%) measuring 2 3 cm. The mean diameters of the HCCs according to degree of cellular differentiation and proportion of degree of cellular differentiation according to tumor size are summarized in Table 1. The visual patterns of tumors were classified as hyperattenuation, isoattenuation, or hypoattenuation and corresponded to the following respective tumor-to-liver differences in attenuation: arterial phase mean attenuation, ± HU, 0.39 ± 5.35 HU, ± 7.18 HU; portal venous phase mean attenuation, ± 7.97 HU, 1.71 ± 5.02 HU, ± HU; equilibrium phase mean attenuation, ± 1.41 HU, 4.35 ± 2.99 HU, ± 8.86 HU. The predominant enhancement patterns of HCC during the arterial and portal venous phases differed significantly depending on tumor size (p = 0.006) and cellular differentiation (p < ) (Figs. 1 4). The proportions of all specific HCC enhancement patterns according to tumor size and cellular differentiation are shown in Table 2. The prevalent enhancing pattern of HCCs mm in diameter was arterial hyperattenuation with venous washout (47%, 47/101), of HCCs smaller than 10 mm was isoattenuation during the arterial and portal venous phases (29%, 6/21) (Fig. 5), and of HCCs measuring mm was hyperattenuation and isoattenuation during the arterial and portal venous phases (33%, 27/82). The proportions of arterial hyperattenuation and washout of HCC according to size and degree of cellular differentiation are summarized in Table 3. Overall, 71% of HCCs smaller than 30 mm in diameter had arterial hyperattenuation, and 37% of HCCs smaller than 30 mm had arterial hyperattenuation followed by washout in the portal venous phase. Although there was no significant difference in proportion of arterial hyperattenuation according to tumor size (p = 0.108), W484 AJR:193, December 2009

4 MDCT of Hepatocellular Carcinoma 2 3 cm 1 2 cm 0 1 cm the proportion of arterial hyperattenuation followed by washout in the portal venous phase differed depending on tumor size (p = 0.015). There was a significantly higher proportion of arterial hyperattenuation followed by washout in the portal venous phase among HCCs with diameters of mm than among HCCs smaller than 10 mm in diameter and HCCs mm in diameter: for 0 9 mm (24%) versus mm (28%) versus mm (47%), p = 0.015; for 0 9 mm versus mm, p = 0.055; and for mm versus mm, p = Furthermore, the predominant enhancement patterns of Proportion With Enhancement Pattern (%) Hyper-Hyper HCC during the arterial and portal venous phases differed significantly depending on the cellular differentiation of the tumor (p = 0.001). The proportions of arterial hyperattenuation were significantly higher for moderately and poorly differentiated HCC than for well-differentiated HCC (well-differentiated vs moderately or poorly differentiated, 52% vs 79%; p = 0.001). In addition, the proportion of tumors with typical HCC enhancement (both arterial hyperattenuation and washout) differed significantly between the well-differentiated HCC group and the moderately or poorly differentiated HCC group 40 Hyper-Iso Hyper-Hypo Iso-Iso Iso-Hypo Hypo-Hypo Fig. 1 Graph shows proportion of hepatocellular carcinomas with enhancement pattern in relation to tumor size. Hyper = hyperattenuating, Iso = isoattenuating, Hypo = hypoattenuating. Well Differentiated Moderately or Poorly Differentiated Proportion With Enhancement Pattern (%) Hyper-Hyper Hyper-Iso Hyper-Hypo Iso-Iso Iso-Hypo Hypo-Hypo Fig. 2 Graph shows proportion of hepatocellular carcinomas with enhancement pattern in relation to cellular differentiation. Hyper = hyperattenuating, Iso = isoattenuating, Hypo = hypoattenuating (well differentiated vs moderately or poorly differentiated, 13% vs 48%; p < ). Tumor size and cellular differentiation were not significant independent variables for the enhancement pattern of HCC except for cellular differentiation of HCC smaller than 2 cm. This result affected the proportion of arterial hyperattenuation followed by washout in the portal venous phase: well differentiated, 9% (4/45) versus moderately or poorly differentiated, 38% (22/58); p = The subgroup analysis of proportion of tumors with typical HCC enhancement features, that is, arterial hyperattenuation followed by washout in the portal venous or equilibrium phase, to determine the value of adding equilibrium phase imaging to biphasic CT showed that adding the equilibrium phase to the arterial and portal venous phases increased the proportion of tumors with typical enhancing features of HCC (arterial hyperattenuation and venous washout) from 48% (36/75) to 56% (42/75), but the difference was not statistically significant (p > 0.05). These results are shown in Table 4. Discussion The widespread use of screening for HCC, including ultrasound examination of patients with cirrhosis according to the guidelines of the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases, has led to an increase in detection of small HCCs [9, 10]. The incidence of HCC in the presence of cirrhosis can exceed 25% 5 years after the diagnosis of cirrhosis, and the sole method of assuring long-term survival is to detect these tumors at an early stage, when effective therapy, such as surgical resection, local ablation, or liver transplantation, is most effective [2, 13, 26]. For these reasons, continued surveillance of patients with cirrhosis is strongly recommended. Although the noninvasive diagnostic criteria for the diagnosis of HCC proposed by the American Association for the Study of Liver Diseases are often used, there is ever-increasing need for radiologists to be able to detect small tumors [6]. Although large nodules are easily diagnosed, the main difficulty in imaging of patients with cirrhosis is characterization of hepatic nodules smaller than 2 cm in diameter [6, 27, 28]. There have been only a few studies of the CT enhancement pattern of small HCC and the percentage of small HCCs that have the typical enhancement pattern of HCC, which is arterial hyperattenuation followed AJR:193, December 2009 W485

5 Yoon et al. A Fig year-old man with liver cirrhosis. A and B, Arterial (A) and portal (B) phase MDCT scans show 1.5-cm hypoattenuating nodule (arrow). Pathologic diagnosis of this hypovascular nodule was well-differentiated hepatocellular carcinoma. A Fig year-old man with viral liver cirrhosis. A and B, MDCT scans show 2.2-cm nodule (arrow) with typical hyperattenuation in arterial phase (A) followed by washout in portal venous phase (B). Nodule was diagnosed as moderately differentiated hepatocellular carcinoma. by washout in the portal venous phase. We evaluated the findings on contrast-enhanced multiphasic MDCT images of a relatively large series of pathologically proven HCCs smaller than 30 mm in diameter. In our study, 71% (144/204) of HCCs had arterial hyperattenuation, and 52% (75/144) of those arterial hyperattenuating tumors exhibited clear washout in the portal venous phase, representing the typical enhancement pattern of HCC [13]. This arterial enhancement of HCC with clear washout in the portal venous phase is consistent with hepatocarcinogenesis, which results in vascular tumor changes toward a predominantly hepatic arterial supply with a lack of portal venous supply B B [29 31]. However, the predominant enhancement patterns of HCC during the arterial and portal venous phases differed significantly depending on tumor size and the cellular differentiation of the tumor. In our study, arterial hyperattenuation was less frequently seen in HCCs smaller than 10 mm in diameter (52%, 11/21) than in HCCs measuring mm (70%, 57/82) or mm (75%, 76/101). Although the MDCT enhancement patterns of small HCCs have rarely been evaluated, our results are similar to those of previous studies [32 34]. Our results differed, however, from those of a previous study of the enhancement pattern of small HCCs at dynamic MRI [35]. In that study, small HCCs (< 20 mm in diameter) often had more intense arterial enhancement than larger-diameter HCCs. We believe that those investigators conclusion is probably correct if enhancement patterns of both small (1 2 cm in diameter) and large (2 25 cm in diameter) HCCs are compared. We believe their conclusion is not the case, however, if many HCCs smaller than 1 cm in diameter are included but not HCCs larger than 3 cm, as was the case in our study. In the previous study, the mean tumor size was 6.85 cm (range, 1 25 cm), and only one HCC was smaller than 1 cm in diameter. Therefore, the discrepancy between our findings and those in the previous study can be attributed to the different tumor diameters of the study samples. In our study, arterial hyperattenuation was found in 53% of well-differentiated HCCs, 79% of moderately differentiated HCCs, and 60% of poorly differentiated HCCs. Our results are similar to the results of a study by Asayama et al. [36]. In that study of the correlation between the arterial bloody supply of HCCs assessed with CT hepatic arteriography TABLE 2: Proportions of Enhancement Patterns of Hepatocellular Carcinoma in Arterial and Portal Venous Phases According to Tumor Size and Degree of Cellular Differentiation Pattern All Tumors (n = 204) 0 9 (n = 21) Tumor Size (mm) (n = 82) (n = 101) Good (n = 63) Cellular Differentiation Moderate (n = 136) Hyperattenuation hyperattenuation 8 (16) 5 (1) 9 (7) 8 (8) 10 (6) 7 (9) 20 (1) Hyperattenuation isoattenuation 26 (53) 24 (5) 33 (27) 21 (21) 30 (19) 24 (34) Hyperattenuation hypoattenuation 37 (75) 24 (5) 28 (23) 47 (47) 13 (8) 48 (65) 40 (2) Isoattenuation isoattenuation 8 (16) 29 (6) 7 (6) 4 (4) 17 (11) 4 (4) 20 (1) Isoattenuation hypoattenuation 12 (25) 19 (4) 12 (10) 11 (11) 19 (12) 9 (13) Hypoattenuation hypoattenuation 9 (19) 11 (9) 10 (10) 11 (7) 9 (11) 20 (1) p < Note Values are percentages with numbers of tumors in parentheses. Percentages do not total 100 owing to rounding. Poor (n = 5) W486 AJR:193, December 2009

6 MDCT of Hepatocellular Carcinoma and histologic grade, well-differentiated HCCs at CT hepatic arteriography often were not found to have an increased arterial blood supply because the neovascular arterial blood supply had increased, even though the normal arterial supply in those nodules had decreased. Moderately differentiated HCCs, however, frequently had an increased arterial supply at A Fig year-old man with viral liver cirrhosis. A and B, Arterial (A) and portal venous (B) phase MDCT scans show tumor (arrow) is isoattenuating and not readily visible. Retrospective review with pathologic information revealed nodule was faintly visible on portal venous phase image. TABLE 3: Proportion of Typical Enhancement Pattern (Arterial Hyperenhancement and Venous Washout) of Hepatocellular Carcinoma According to Tumor Size and Degree of Cellular Differentiation Tumor size (mm) Variable CT hepatic arteriography. Also in that study, in the late stage of HCC development (poorly differentiated HCC), the arterial blood supply decreased significantly as histologic grade progressed. Other previous studies [6, 12, 37] of CT during arterial portography and CT during hepatic arteriography and with pathologic correlation have shown that as the grade B of malignancy within a nodule increases, the normal hepatic arterial and portal venous supply to the nodule gradually decreases, and the decrease is followed by an increase in abnormal arterial supply through the newly formed abnormal arteries (neoangiogenesis). Our data show that when the noninvasive imaging diagnostic criteria for HCC proposed by the American Association for the Study of Liver Diseases were applied to the small HCCs in our study, only approximately one fourth of the HCCs smaller than 20 mm in diameter and less than one fifth of the well-differentiated HCCs with typical arterial hyperattenuation followed by washout were diagnosed with MDCT. Although our study showed the proportion of HCCs smaller than 20 mm in diameter that can be diagnosed with MDCT according to the guidelines of the American Association for the Study of Liver Diseases, these results are similar to the HCC detection rate with dynamic MRI [13, 38]. In addition, our results strongly agreed with those of a study by Jang et al. [28], who evaluated contrast-enhanced ultrasound. Those investigators found that when the tumor is small or well differentiated, the proportion of atypical enhancement pattern of HCC on contrast-enhanced ultrasound images increases. Because only 24% of HCCs smaller than 10 mm in our study had the typical HCC enhancement pattern, that is, a combination of arterial hyperattenuation and washout in the portal venous phase, and because many small hyperattenuating lesions smaller than 1 cm in diameter were benign hepatic lesions even in patients with cirrhosis [29, 31, 39], we believe that when the tumor diameter is less than 10 mm, with current imaging techniques it continues to be difficult to make a noninvasive imaging diagnosis of HCC solely on the basis of vascular changes. Concern over the increase in hypovascular HCC has been increasing [11] and has been brought to the attention of both radiologists and hepatologists. Bolondi et al. [11] found TABLE 4: Enhancement Pattern of Hepatocellular Carcinomas Smaller Than 30 mm in Diameter on Triphasic Phase CT Scans Imaging Technique Arterial Hyperenhancement Venous Washout of Hypervascular Tumor All tumors 71 (144/204) 37 (75/204) (11/21) 24 (5/21) (57/82) 28 (23/82) (76/101) 47 (47/101) p Cellular differentiation Well differentiated 52 (33/63) 13 (8/63) Moderately or poorly differentiated 79 (111/141) 48 (67/141) p < Note Values are percentages with numbers of tumors in parentheses. Percentage With Arterial Hyperenhancement Followed by Venous Washout in Portal Venous Phase or Equilibrium Phase (n = 75) Combination of arterial and portal venous phases 48 (36) Combination of arterial and equilibrium phases 53 (40) a Combination of arterial, portal venous, and equilibrium phases 56 (42) b Note Numbers in parentheses are the numbers of tumors. a Difference between combined set of arterial and portal venous phase images and combined set of arterial and equilibrium phase images. b Difference between combined set of arterial and portal venous phase images and combined set of arterial, portal venous, and equilibrium phase images. p AJR:193, December 2009 W487

7 Yoon et al. that if even a small nodule in a cirrhotic liver does not exhibit contrast uptake in the arterial phase, its malignant nature cannot be ruled out, and further exploration should be conducted. Because a small number of HCCs smaller than 20 mm in diameter that are well differentiated do not have the typical vascular changes of HCC and therefore exhibit atypical enhancement patterns at dynamic CT and MRI, further studies are needed to evaluate the nonvascular findings of HCC with liver-specific MRI contrast agents, such as superparamagnetic iron oxide and gadoxetic acid [40]. There were limitations to our study. First, it was limited by its retrospective nature and our limited control over patient selection. For pathologically proven HCCs smaller than 30 mm in diameter on contrast-enhanced multiphasic MDCT scans, however, our series was relatively large, and patient selection was consecutive. Second, although the diagnosis of HCC was established mainly at liver resection or transplantation, 35 patients underwent liver biopsy to establish the diagnosis of HCC. It is difficult, however, to distinguish well-differentiated HCC from dysplastic nodules in small biopsy specimens because there is not a clearcut dividing line between a dysplastic nodule and welldifferentiated HCC [32]. It is possible, therefore, that a percutaneous liver biopsy specimen may not represent the true pathologic grading of the nodules. However, in all of our study patients, we performed core biopsy using an 18-gauge needle and obtained at least two samples of the tumor and the adjacent liver parenchyma. A third limitation was that although several studies have shown the value of equilibrium phase imaging for visualizing HCC washout and increasing specificity [10, 11, 33], equilibrium phase dynamic CT images were obtained for only 69 patients with 75 HCCs. For 129 HCCs in 86 patients, we could not evaluate the enhancement pattern of HCC during the equilibrium phase. However, our subgroup analysis with the patients who underwent triphasic MDCT showed results statistically similar to those for the patients who underwent biphasic MDCT. Nonetheless, there might have been a slightly higher incidence of typical arterial hyperattenuation followed by washout of small HCCs with the addition of equilibrium phase acquisition. Fourth, different types of MDCT scanners and different CT variables were used. However, because more than 30 liver CT examinations are performed daily at our center to evaluate cirrhosis, the scanning protocol is well established. Furthermore, although the detector collimation differed for each scanner, the reconstruction slice thicknesses were similar ( mm). We believe that 3 5 mm is an acceptable reconstruction slice thickness for liver CT; 3 or 4 mm is used at many centers. We conclude that the predominant enhancement patterns of small HCC (< 30 mm in diameter) at multiphasic MDCT differed according to tumor size and cellular differentiation. HCCs larger than 20 mm that were moderately or poorly differentiated generally had classic enhancement features, but well-differentiated and small HCCs more often had atypical enhancement features. An awareness of the characteristic enhancement patterns of small HCC in cirrhotic liver may aid in reaching the correct diagnosis and selecting the appropriate treatment. Further studies of the nonvascular findings of HCC with a liver-specific MRI contrast agent, such as superparamagnetic iron oxide or gadoxetic acid, or a functional study with diffusion-weighted MRI or elastography are needed to improve the noninvasive diagnosis of HCC. Acknowledgment We thank Bonnie Hami for help in manuscript editing. References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan Int J Cancer 2001; 94: Tsukuma H, Hiyama T, Tanaka S, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993; 328: Velazquez RF, Rodriguez M, Navascues CA, et al. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis. Hepatology 2003; 37: Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology 1998; 27: Willatt JM, Hussain HK, Adusumilli S, Marrero JA. MR Imaging of hepatocellular carcinoma in the cirrhotic liver: challenges and controversies. Radiology 2008; 247: El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008; 134: Marrero JA, Hussain HK, Nghiem HV, Umar R, Fontana RJ, Lok AS. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass. Liver Transpl 2005; 11: Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35: Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42: Bolondi L, Gaiani S, Celli N, et al. Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma. Hepatology 2005; 42: Kudo M. Imaging diagnosis of hepatocellular carcinoma and premalignant/borderline lesions. Semin Liver Dis 1999; 19: Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008; 47: Hayashida M, Ito K, Fujita T, et al. Small hepatocellular carcinomas in cirrhosis: differences in contrast enhancement effects between helical CT and MR imaging during multiphasic dynamic imaging. Magn Reson Imaging 2008; 26: Yumoto Y, Hanafusa T, Hada H, et al. Loss of heterozygosity and analysis of mutation of p53 in hepatocellular carcinoma. J Gastroenterol Hepatol 1995; 10: Barbara L, Benzi G, Gaiani S, et al. Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 1992; 16: Okazaki N, Yoshino M, Yoshida T, et al. Evaluation of the prognosis for small hepatocellular carcinoma based on tumor volume doubling time: a preliminary report. Cancer 1989; 63: Itoh S, Ikeda M, Achiwa M, Satake H, Iwano S, Ishigaki T. Late-arterial and portal-venous phase imaging of the liver with a multislice CT scanner in patients without circulatory disturbances: automatic bolus tracking or empirical scan delay? Eur Radiol 2004; 14: Takahashi S, Murakami T, Takamura M, et al. Multi-detector row helical CT angiography of hepatic vessels: depiction with dual-arterial phase acquisition during single breath hold. Radiology 2002; 222: Loyer EM, Chin H, DuBrow RA, David CL, Eftekhari F, Charnsangavej C. Hepatocellular carcinoma and intrahepatic peripheral cholangiocarcinoma: enhancement patterns with quadruple phase W488 AJR:193, December 2009

8 MDCT of Hepatocellular Carcinoma helical CT a comparative study. Radiology 1999; 28. Jang HJ, Kim TK, Burns PN, Wilson SR. En imaging. Abdom Imaging 1999; 24: : hancement patterns of hepatocellular carcinoma 35. van den Bos IC, Hussain SM, Dwarkasing RS, et 21. Lee KH, O Malley ME, Haider MA, Hanbidge A. at contrast-enhanced US: comparison with histo al. MR imaging of hepatocellular carcinoma: re Triple-phase MDCT of hepatocellular carcinoma. logic differentiation. Radiology 2007; 244:898 lationship between lesion size and imaging find AJR 2004; 182: ings, including signal intensity and dynamic en 22. Awai K, Inoue M, Yagyu Y, et al. Moderate versus 29. Hwang SH, Yu JS, Kim KW, Kim JH, Chung JJ. hancement patterns. J Magn Reson Imaging 2007; high concentration of contrast material for aortic Small hypervascular enhancing lesions on arterial 26: and hepatic enhancement and tumor-to-liver contrast at multi-detector row CT. Radiology 2004; 233: Awai K, Takada K, Onishi H, Hori S. Aortic and hepatic enhancement and tumor-to-liver contrast: analysis of the effect of different concentrations of contrast material at multi-detector row helical CT. Radiology 2002; 224: Baron RL. Understanding and optimizing use of contrast material for CT of the liver. AJR 1994; 163: Choi SH, Han JK, Lee JM, et al. Differentiating malignant from benign common bile duct stricture with multiphasic helical CT. Radiology 2005; 236: Colombo M, Donato MF. Prevention of hepatocellular carcinoma. Semin Liver Dis 2005; 25: Choi D, Mitchell DG, Verma SK, et al. Hepatocellular carcinoma with indeterminate or false-negative findings at initial MR imaging: effect on eligibility for curative treatment initial observations. Radiology 2007; 244: phase images of multiphase dynamic computed tomography in cirrhotic liver: fate and implications. J Comput Assist Tomogr 2008; 32: Lee J, Lee WJ, Lim HK, et al. Early hepatocellular carcinoma: three-phase helical CT features of 16 patients. Korean J Radiol 2008; 9: Shimizu A, Ito K, Koike S, Fujita T, Shimizu K, Matsunaga N. Cirrhosis or chronic hepatitis: evaluation of small ( 2 cm) early-enhancing hepatic lesions with serial contrast-enhanced dynamic MR imaging. Radiology 2003; 226: Hytiroglou P, Park YN, Krinsky G, Theise ND. Hepatic precancerous lesions and small hepatocellular carcinoma. Gastroenterol Clin North Am 2007; 36: Monzawa S, Ichikawa T, Nakajima H, Kitanaka Y, Omata K, Araki T. Dynamic CT for detecting small hepatocellular carcinoma: usefulness of delayed phase imaging. AJR 2007; 188: Monzawa S, Omata K, Shimazu N, Yagawa A, Hosoda K, Araki T. Well-differentiated hepatocellular carcinoma: findings of US, CT, and MR 36. Asayama Y, Yoshimitsu K, Nishihara Y, et al. Arterial blood supply of hepatocellular carcinoma and histologic grading: radiologic pathologic correlation. AJR 2008; 190:90; [web]w28 W Choi BI, Takayasu K, Han MC. Small hepatocellular carcinomas and associated nodular lesions of the liver: pathology, pathogenesis, and imaging findings. AJR 1993; 160: Taouli B, Krinsky GA. Diagnostic imaging of hepatocellular carcinoma in patients with cirrhosis before liver transplantation. Liver Transpl 2006; 12[11 suppl 2]:S1 S7 39. Holland AE, Hecht EM, Hahn WY, et al. Importance of small (< or = 20-mm) enhancing lesions seen only during the hepatic arterial phase at MR imaging of the cirrhotic liver: evaluation and comparison with whole explanted liver. Radiology 2005; 237: Kudo M, Okanoue T. Management of hepatocellular carcinoma in Japan: consensus-based clinical practice manual proposed by the Japan Society of Hepatology. Oncology 2007; 72[suppl 1]: 2 15 AJR:193, December 2009 W489